Cerebrum

Migraine’s Long Road to Respect

What brain disorder disrupts the lives of millions of Americans, many in their thirties and forties, throwing home life into chaos and exacting a $13-billion annual toll in lost or reduced workplace productivity? The answer is migraine.

But the larger question is why it has taken doctors and the public so long to take migraine headaches seriously, says Mayo Clinic headache researcher David Dodick. New brain research challenges both the view that migraine is a personality problem and the 400-year-old theory, still common, that migraine can be understood in terms of contracting and dilating blood vessels. As scientists have sought the origins of migraine in the brain, doors have opened to truly effective treatments for many headache sufferers.

From the ancient civilization of Mesopotamia to modern America, headache has been among the most common medical complaints. Today, in one of its most severe and disabling forms— migraine—it afﬂicts 28 million Americans, the majority in the prime of life, and its annual economic impact from lost work and reduced productivity is estimated at $13 billion. Strangely, neither time nor the toll of suffering and disability has dislodged the stubborn notion, held by the general public and physicians alike, that migraine and other forms of headache are the “common cold” of neurologic problems. “For I had no brain tumor, no eyestrain, no high blood pressure, nothing wrong with me at all,” writes Joan Didion. “I simply had migraine headaches, and migraine headaches were, as everyone who did not have them knew, imaginary.”

For some decades, much of what passed for research on headaches was a search for particular personality traits of migraine patients, on the assumption that a “migraine personality” might be the problem. The verdict? Migraine sufferers were rigid, compulsive, insecure, perfectionist, sensitive to criticism, ambitious, competitive, chronically resentful, and deeply frustrated emotionally. For good measure, they were mostly female, women being known to suffer from migraine at a rate three times that of males. The stereotype—and the grounds for dismissal—was complete.

Now, one of medicine’s long-misunder-stood disorders is ﬁnally yielding to advances in molecular biology and brain imaging that have demystiﬁed other diseases by unveiling their basis in the brain. Today a powerful case can be made that migraine is an inherited, highly disabling, unpredictable neurological disorder caused by speciﬁc mechanisms in the brain. The good news is that progress in migraine treatment over the past decade bodes well for the headache sufferer. The next step, by no means easy or quick, will be to reach the estimated half of all migraine sufferers who are never diagnosed or professionally treated.

EVIL SPIRITS, NOXIOUS VAPORS, AND VASCULAR SPASMS

Like medicine itself, management of migraine has moved from the temple to the clinic and laboratory, and treatment has left the realm of magic and entered the age of molecular biology. In civilizations of the ancient world, including Mesopotamia, Egypt, India, and Greece, headaches were believed to be the work of malevolent beings who occupied the skull of the sufferer or implanted the headache as an entity into the head. Treatment by the priest-physician aimed at appeasing the responsible spirit by offering prayers to it or applying valued items to the sufferer’s head. Another strategy was to exorcise the headache by appeals to more powerful and benevolent deities or by adorning the head with repulsive substances.

Perhaps this approach relieved the headache by placebo effect or because a tight bandage compressed distended scalp arteries. When it failed, however, recourse was to releasing the evil spirit through a hole gouged in the patient’s skull. Neolithic skulls dating from 7000 B.C. show evidence of new bone growth at the margins of the holes, suggesting that some patients survived the ministrations of Stone Age neurosurgeons. The technique, known as trephination, was used to treat migraine as late as the mid-17th century.

Neurologists owe a singular debt to Hippocrates, who practiced about 400 B.C., as he not only recognized the syndrome called migraine but ascribed it to an imbalance of natural forces within the body instead of to the inﬂuence of supernatural beings.An essential step toward rational therapy was distinguishing speciﬁc maladies within the vast universe of headaches. Neurologists owe a singular debt to Hippocrates, who practiced about 400 B.C., as he not only recognized the syndrome called migraine but ascribed it to an imbalance of natural forces within the body instead of to the influence of supernatural beings. He wrote, describing a young patient:

Most of the time he seemed to see something shining before him like a light, usually in part of the right eye. At the end of a moment, a violent pain supervened in the right temple, then in all the head and neck, where the head is attached to the spine. Vomiting, when it became possible, was able to divert the pain and render it more moderate.

It was Galen, in the second century A.D., who attached a name to the afﬂiction.

He wrote of “a painful disorder affecting approximately one-half of the head, either the right side or the left side, and which extends along the length of the longitudinal suture.” His term for this, “hemicrania,” was gradually transformed into “migraine.” Like Hippocrates, Galen believed that this type of headache and its accompaniments were caused by the ascent of vapors from the liver to the head, which explained the conjoining of vomiting and headache. Galen’s concept survives in the lay term “bilious headache.”

The Greek concept of migraine continued into the 17th century, when the master clinician Thomas Willis combined his unique clinical acumen and meticulous anatomic dissection to revolutionize thinking about migraine. In Dr. Willis’ Practice ofPhysicke, published in 1684, nine years after Willis died, headache is attributed to increased blood ﬂow to the head, which “distends the vessels, greatly blows up the membranes, and pulls the nervous ﬁbres one from another, and so brings to them painful corrugations or wrinklings.”

This vascular theory of migraine was not questioned for a century. Edward Lieving was an early proponent of the view that the complexity of the migraine syndrome could not be generated by crude physiologic changes such as expanding and contracting blood vessels. In 1893, he wrote in his classic monograph, A Contribution to the Pathology of Nerve Storms, that “We must not assign too much signiﬁcance to throbbing, or to the increase in the pain by the causes of vascular distention; these may be due merely to the oversensitiveness of the central structures.”

Despite this prophetic pronouncement, the vascular theory enjoyed a resurgence in the twentieth century and dominated neurology until the 1980s. This resulted in large measure from the experiments of Harold Wolff and his colleagues, who concentrated on the reactions of blood vessels during migraine. Since drugs that caused dilation of these arteries could reliably precipitate migraine, and drugs that caused arteries to constrict brought relief, migraine seemed obviously a disorder of the cerebral blood vessels. In fairness to Wolff, he did leave open the possibility that vascular changes were secondary to changes occurring in the brain.

Only the era of molecular biology and functional neuroimaging in the last quarter of the twentieth century has given us insights into the pathophysiology of migraine as a brain disorder, or what is now referred to as a neurovascular syndrome, rather than a vascular headache. This term accurately names the brain as the site where the process is initiated, leading to the transmission of impulses along nerve ﬁbers that leave the brain and become imbedded in the cerebral blood vessels. When the contents located at the terminal end of this nerve ﬁber are released, the effects on the blood vessel become a downstream effect of events that are taking place in the brain. These insights have provided the knowledge needed to ﬁnd effective drug treatments to relieve the suffering of migraine patients.

THE LONG ROAD TO RESPECT

In spite of remarkable recent advances in understanding and treating migraine, the public and the medical profession still seem to cling to the notion that little is known about migraine and even less can be done about it. The common attitude is that migraine is just a bad headache that occupies far more of a busy doctor’s time than its importance warrants. Worse still is the pervasive, underlying tone of skepticism captured in the earlier quotation from Joan Didion.

Women in particular have been the target of disparaging epithets that reﬂect how deeply misunderstood is this afﬂiction. In 1764, Dr. Robert Whytt in his monograph Observations...Disorders Commonly Called Nervous, described it as a disorder of “women, in whom the nervous system is generally more moveable than in men and are more subject to nervous complaints.” The diminishment of headache’s seriousness can be found in everyday colloquialisms (“These meetings are a real headache”) and in the modern-day thesaurus, which offers “headache” as a synonym for worry, nuisance, or annoyance.

The interaction of psychology and physiology in migraine has been more obscured than clariﬁed by reports over the years on supposed personality traits of migraine patients. The notion of a “migraine personality” ﬁrst arose out of clinical observations of highly selected patients seen in subspecialty clinics. Studies over the last two decades do, in fact, report an association between migraine and neurosis, but most of these studies did not control for drug use, headache frequency, and headache-related disability. Nor did they control for serious psychiatric disorders such as major depression, anxiety, and panic disorder, which occur more commonly in patients with migraine. In short, the stereotypical rigid, obsessional migraine personality may reﬂect the selection bias of a distinct subtype of migraine most often seen in subspecialty headache clinics, whose patients are not representative of the general population of migraine sufferers.

Unfortunately, this stereotype of a migraine personality became common currency in the medical community and contributed in no small degree to the ambivalent, skeptical, and helpless attitude with which many physicians continue to approach migraine patients. Even among neurologists, for whom migraine and headaches as a whole are the most common reason for consultation, headache sufferers are rarely viewed as interesting or professionally rewarding patients. I have found such doctors on more than one occasion lamenting that it takes a special kind of person to see these patients. As such, my colleagues thoughtfully try to balance their desire to refer as many headache patients as possible to me with their guilt at burdening me with them.

Through it all, the perception that migraine is a signiﬁcant, legitimate, biological disorder, for which there are increasingly effective treatments, is ﬁnally beginning to take hold. Together with remarkable scientiﬁc insights into its neurobiological basis and effective treatment, the respect that this disorder so desperately deserves is at last emerging—and not a moment too soon for the millions afﬂicted by it.

A PLAGUE OF PAIN

Solid information on the scope and impact of migraine has come to us relatively recently. The 1989 American Migraine Study conducted by Richard Lipton and Walter Stewart was the ﬁrst in this country to use standard diagnostic criteria to deﬁne cases of migraine and estimate its prevalence. This study revealed that 18 percent of women and 6 percent of men—a total of 23 million Americans in 1989—suffered from severe migraine headaches. That prevalence was recently conﬁrmed by the 1999 American Migraine Study II, which included a survey of 20,000 households representative of the general population. In addition to varying by sex, migraine’s prevalence varied with age (highest in 35to 45-year-olds); household income (highest in the lowest income group, which earned less than $10,000 annually); and race (higher in Caucasians than African-Americans). These ﬁndings have been corroborated by other studies in the United States, Germany, France, and Canada.

The American Migraine Study II also revealed that severe migraine episodes are associated with marked debilitation. More than half of migraine sufferers reported substantial impairment in activity or the necessity for bed rest when severe headaches struck, and almost one-third reported that a severe headache forced them to restrict their activities for one to two days. Work or school productivity was reduced by at least half among 51 percent of migraine sufferers. Family, social, and household activities were even more vulnerable to disruption by migraine. The results of this study, which demonstrate a considerable impact of migraine on functional ability, are consistent with the results of other population-based studies and clinical trials showing that migraine impairs workplace productivity and limits one’s ability to participate in family and leisure activities.

Considering that one in four households in the United States has a migraine sufferer, the economic and public health implications of this disability are staggering. This is especially true since the peak prevalence of migraine in both women and men occurs during the traditionally most productive years of life. Of the 28 million Americans who were estimated to suffer from severe migraine headaches in 1999, an estimated 14.8 million experienced pain severe enough to substantially impair their normal daily activities or to require them to take to their beds. Indeed, migraine accounts for approximately 112 million bedridden days per year. The resulting missed work and reduced function of migraine sufferers on the job translates into a $13 billion price tag to American employers.

If anything, these huge numbers may underestimate the prevalence and impact of migraine because they were derived from people who reported severe headaches; responses from people suffering mild or moderate headaches or minimal disability were not solicited. Furthermore, people who have headaches every day were also excluded from this study. Recent estimates indicate that there may be more than 12 million Americans who suffer from headaches every day of their lives—a group of highly disabled patients who were not included in the American Migraine Studies.

Despite its pervasiveness and disability, migraine has been underrecognized and undertreated, a trend that continues today. If one looks at the patterns of migraine consultation, diagnosis, and medication use in the United States in the 1989 and 1999 American Migraine Studies, one will ﬁnd that more people have sought help for and been diagnosed with migraine over the past decade, but many still do not consult a physician and approximately half of all cases go undiagnosed. Even though the rates of consultation and diagnosis have increased (slightly) over this 10-year period, the use of prescription medications for migraine management has not increased over the past decade, despite the availability of signiﬁcantly superior treatments. The unfortunate result is that less than one-third of migraine sufferers report themselves “very satisﬁed” with their treatment.

With the advances in our understanding and the emergence of effective treatment, how can a medical disorder that impairs the quality of life of so many continue to be misunderstood, poorly recognized, under-treated, and often dismissed as psychosomatic? There is certainly no single or simple reason. However, inadequate undergraduate medical training is responsible, at least in part. Traditionally, physicians have not received formal education or training in the diagnosis and management of pain in general, much less headache in particular. This is ironic, especially since headache is one of the most common complaints they will address on a daily basis in their clinical practice. To complicate matters, pain is a subjective symptom, and headache diagnosis is based on clinical features and cannot be objectively measured by a blood test or identiﬁed by an X-ray.

Headache is frequently accompanied by feelings of sadness, anxiety, and irritability —responses that are biologically unavoidable, but often misinterpreted as the cause of the pain or the result of a weak constitution. This misconception is promulgated by the frequent triggering of an attack by emotional stress. Since stress is a ubiquitous human experience, with innumerable ways in which it can become physically manifest in any given individual (racing heart, sweaty palms, a rise in blood pressure, facial ﬂushing, hyperactive bowel), it should come as no surprise that a migraine attack is simply another manifestation that can occur in a genetically predisposed individual, and that this response is based on the hard-wiring of the brain. However, this poorly understood concept underlies the frequent dismissal of headache of any type as a purely psychosomatic illness and accounts, in the words of Oliver Sacks, for the current inelegant cliché of “learning to live with it as advised by the physician, who hopes that he will not be on duty the next time the patient comes for advice...[D]espite the complexities and variabilities of a condition which is in every way fascinating in its phenomenology, many doctors are only too pleased when a patient, in desperation, takes himself off to the practitioners of fringe medicine.”

HOW DOES THE BRAIN CREATE MIGRAINE?

Just as the vascular theory of migraine has held court since Willis’s day in the 1600s, so “vascular headache” is lodged in the medical lexicon and physician’s everyday vernacular. Indeed, the term has evolved to encompass not only migraine but any headache that throbs or pulsates. If such a headache can be tied in any way to the ubiquitous human experience of stress, that headache becomes a “tension-vascular headache” to many physicians. This usage not only minimizes the complexity of this neurological disorder, it leads to erroneous diagnoses, and, ultimately, promotes misguided therapy.

For almost two thousand years, the term “aura” has been used for the sensory hallucinations experienced just before certain epileptic seizures. For a century or more, the term has also been applied to similar symptoms that seem to presage certain migraine attacks. Unquestionably, these transient neurologic symptoms are among migraine’s most striking features and certainly one that motivates patients to consult a physician.

The most common aura is a visual hallucination: a dance of brilliant stars, sparks or ﬂashes of light, blind spots, and complex geometric patterns. Other symptoms may include a tingling in the face and upper extremity, speech impairment, or weakness of one side of the body (hemiparesis). When present, these symptoms usually precede the headache phase by 20 to 60 minutes, although they may occur at the beginning of or during the headache, or may even occur in isolation with no headache following. According to the hallowed vascular theory, the symptoms of the migraine aura are caused by constriction of blood vessels, resulting in obstruction of blood and thus a shortage of oxygen to the brain. On this theory, the headache that follows is a result of a dilation of large blood vessels within the head—a response to the presumed demand for blood and oxygen brought about by the constriction phase.

This theory does not explain key clinical features of migraine. Consider four of these features. First, aura is experienced by only 15 percent of migraine patients, and even then during only some attacks. Second, the majority of migraine patients report a constellation of warning symptoms that precede their headache by hours or days: ﬂuid retention, thirst, food cravings, elation, depression, and drowsiness. It is impossible to account for these diverse symptoms on the basis of the obstruction of cerebral blood vessels. Third, medications such as nonsteroidal anti-inﬂammatory agents, neuroleptic agents, and the anti-epileptic drug divalproex sodium do not constrict dilated blood vessels, yet they are very effective in relieving the headache and its associated symptoms. Finally, functional brain imaging studies reveal not only that the headache phase of migraine begins while cerebral blood ﬂow is still reduced (not increased as one would expect if blood vessels were dilated), but that the earliest phase of the aura is associated with an increase, not a decrease, in cerebral blood ﬂow.

Let us look at this ﬁnal point in more detail. Key research using single photon emission computed tomography (SPECT) has shown that the migraine aura is associated with a reduction in cerebral blood ﬂow (called oligemia) that moves across the patient’s cerebral cortex (brain surface) at a rate of two to three millimeters a minute, like a shadow slowly sweeping across the landscape. This is consistent with an earlier rather extraordinary calculation by Karl Lashley, a Harvard neurophysiologist of the mid-twentieth century, who observed his own migraines and noted that the growth of his visual aura seemed to correspond to an event moving across his cortex at the same rate— two to three millimeters a minute. Still earlier research by A.A.P. Leao found that noxious stimulation of the exposed cerebral cortex of a rabbit produced a decrease in electrical activity that swept across the cerebral cortex. The rate? Again, two to three millimeters per minute. That the rates of spreading oligemia, visual aura, and spreading cortical depression of electrical activity are all equivalent strongly suggest that they are related phenomena.

Curiously, this phase of spreading oligemia, or reduced cerebral blood ﬂow, is preceded by a phase of increased cerebral blood ﬂow. This makes it highly unlikely that the observed reduction in cerebral blood ﬂow results from a constricting of blood vessels. It makes it equally unlikely that the headache following aura results from a dilation of the vessels in reaction to the constriction, since the headache pain begins during the time when cerebral blood ﬂow is still reduced. Similar observations of blood ﬂow have been made using more sophisticated imaging modalities, such as positron emission tomography (PET) and high-ﬁeld functional MRI, with near continuous recording of the ﬂow during visual aura in patients with migraine.

A recent study by scientists at Harvard University demonstrated that depressed electrical activity moving across the cortex explains the phenomena of the migraine visual aura. The conclusion from this and other brain imaging studies is that the migraine aura is not evoked by constriction of blood vessels that obstructs oxygen-carrying blood. Instead, it is probably evoked by aberrant ﬁring of neurons and related cellular changes that are characteristic of what we call “cortical spreading depression”—a reduction of electrical activity moving slowly across the patient’s cerebral cortex. Changes in blood ﬂow actually develop not as a cause, but as a consequence of these changes in neuronal activity that occur during the visual aura.

If reduction of electrical activity (cortical spreading depression) is the villain that causes migraine aura, what sets it off? No one is sure, as yet, but there is evidence for the idea that some people may have over-excitable specialized neurons in the visual cortex. Lowering the threshold for activation of those neurons might create the conditions for aura.

Evidence for this state of neuronal hyperexcitability in some migraine patients is both neurophysiologic and genetic. Studies of the brain’s occipital cortex in patients who have migraine with aura show that they have much lower thresholds for stimulating the generation of visual sparks than control subjects do. Genetic evidence supporting this theory focuses on abnormalities in neuronal calcium channels. These channels are pores on the outer membrane of neurons that are voltage-gated, that is, the opening and closing of these channels are dependent on the electrical charge of the cell membrane. Inﬂux of calcium leads to a variety of changes within the cell, including the release of chemical neurotransmitters that interact with and change the excitability and activity of other brain cells. Recently, a genetic mutation on chromosome 19 that encodes for the pore-forming unit of the neuronal P/Q calcium channel was shown to be involved in one type of migraine (familial hemiplegic migraine). This same chromosomal region may also be involved in migraine that is associated with other types of aura as well. A calcium channel crucial to the functioning of neurons may be genetically altered in some patients in a way that facilitates the initiation of aura by increasing their susceptibility to spreading excitation followed by spreading cortical depression.

All of this, however, relates to aura, only one of the striking characteristics of migraine. What about the feature of migraine that concerns every patient and family: pain?

THE SOURCES OF PAIN

Our understanding of the biology of migraine aura has been enhanced by elegant functional brain imaging studies during migraine attacks—but unfortunately we still do not know how these cortical changes give rise to head pain. What is more, because aura occurs in only 15 to 20 percent of patients, and only during some of their attacks, the origin of the headache phase of migraine remains an area of intensive investigation by scientists.

What we understand thus far about how pain begins during a migraine attack relates to the anatomy and physiology of the trigeminal nerve at the base of our brains and the blood vessels to which they attach. Pain during migraine seems to be produced in two ways. The ﬁrst is activation of the trigeminal nerve ﬁbers that connect with pain-producing blood vessels and the outer covering of the brain inside the skull. The second is reduction in the functioning of our built-in pain-control pathways, which normally inhibit the transmission of pain to higher centers in the nervous system. Let us look at each of these.

The ﬁbers of the trigeminal nerve that connect with cerebral blood vessels originate in neurons within the trigeminal nerve cell body, or ganglion. The nerve contains chemicals called neuropeptides that are released when the nerve is stimulated during experiments and during acute migraine attacks. Release of these chemicals from the nerve endings leads to painful dilation of cerebral blood vessels and possibly to inﬂammation surrounding these blood vessels. This activates the central pain-transmitting and-receiving neurons to which they connect. Ultimately, the resulting pain signals are processed in the sensory cortex of the brain and perceived as the throbbing pain that has become a signature of migraine.

What about our systems for inhibiting or generating pain? Normally, upward transmission of pain to the brain is modulated by a downward inhibitory pain-control system originating in the brain stem. In one of the most important and provocative studies in the ﬁeld of migraine research in recent years, Weiller and Diener at the University of Essen used PET scanning to observe activation of part of the brain stem during migraine attacks without aura. Not surprisingly, other areas of the brain that are responsible for the normal processing of pain—including the cingulate and insular association cortices—were also activated. The most interesting discovery from this study was that the brainstem structures, but not the cortical structures, remained activated after the headache was over. This has been corroborated by a very recent study; the activated area corresponds to the same region that had been shown to cause migraine-like headaches when stimulated in patients who had electrodes implanted for pain control for conditions other than headache. This suggests that there are brain stem regions that play a pivotal role in initiating or terminating acute migraine attacks and has led to its designation as a potential “migraine generator.”

GOOD AND GETTING BETTER: TREATMENT OF MIGRAINE

Understanding the role in the origin of migraine headache played by the trigeminal nerve, related blood vessels, and serotonin receptors opened the door to developing a family of compounds that have revolutionized the treatment of migraine. These drugs, called triptans, are truly designer pharmaceuticals, the ﬁrst compounds speciﬁcally created for treatment of migraine. Because they target vascular and neural receptors found primarily within the trigeminovascular system, they do not affect pain other than headache and so are referred to as migraine-speciﬁc.

Triptans seem to work by activating speciﬁc serotonin receptors that are located on both cerebral blood vessels and trigeminal nerve ﬁbers. One effect is to cause dilated cerebral blood vessels to constrict; another is to decrease activity in the trigeminal pathway and inhibit the release of neuropeptides that cause inﬂammation and dilation of these blood vessels. Thus the triptans narrowly target the brain events that are directly responsible for head pain during migraine attacks. In most cases, the pain and associated symptoms such as nausea are relieved within two hours.

Alas, we cannot end the story on that note. For reasons not yet clear, the triptans do not work for some patients; for others, the headache returns quickly after initial relief. Also, because they have the potential to constrict the coronary arteries, there is concern over the potential for adverse side effects on the heart. In exceedingly rare cases—less than one in a million—a heart attack has occurred shortly after taking sumatriptan, the first triptan to receive FDA approval in 1991. Therefore these medications are contraindicated in patients with cardiovascular disease or signiﬁcant cardiovascular risk.

PREVENTING ATTACKS

Although the triptans have given many patients relief from migraine attacks, similar strides have not been made in preventing them from occuring in the ﬁrst place.

The goal is to prevent the central processes involved in initiating a migraine attack. Many drugs now available do reduce by half the frequency of migraine attacks in about 40 to 50 percent of patients. Most commonly used are anticonvulsants, beta-blockers, and tricyclic antidepressants. The anticonvulsants—including divalproex sodium, gabapentin, and topiramate—are thought to work by enhancing the activity of certain inhibitory pathways. This is presumed to decrease the hyperexcitability of central neurons that may characterize the brains of those with migraine. This in turn may inhibit the initiation of cortical or brain stem events that generate a migraine attack. Beta-blockers and tricyclic antidepressants have many effects on many receptors and sites in the brain; precisely how they act on migraine is unknown.

AN ERA OF TRIAL AND ERROR

Research on new drugs to treat migraine is proceeding on many fronts. Recent research has focused on the receptors located on trigeminal nerve endings, which, when activated, stimulate the release of neuropeptides that can lead to painful dilation of cerebral blood vessels and activation of central pain neurons. One of these neuro-peptides, known as CGRP, is selectively elevated during migraine attacks and represents the most potent blood vessel-dilation agent in the human body. Substances that appear to block the effects of CGRP are in late-stage clinical trials in people with migraine. The results of these studies are eagerly awaited, but the strategy of blocking the effect of a single neuropeptide like CGRP has a downside, of course. You block only one of many neuropeptides that may be involved in causing migraine, and you have an effect only after the trigeminal nerve has been activated—in other words, after the trouble has begun. A broader approach would be to target receptors on trigeminal nerve terminals in order to prevent the release of all substances that could potentially wreak havoc. A possibility is to activate serotonin receptors located on trigeminal nerve terminals, but not on cerebral or coronary blood vessels. Such a selective serotonin agonist showed signiﬁcant promise in clinical migraine trials, but has been withdrawn because of liver toxicity in animals.

Finally, a variety of other receptors located on peripheral and central trigeminal nerve terminals and neurons are prime targets for acute migraine therapies. One very recent clinical trial of a compound that blocks the activation of a glutamate receptor (NMDA) located on the trigeminal nerve and nucleus in the brainstem, demonstrated robust efﬁcacy for the acute relief of migraine headache and associated symptoms.

Glutamate is an excitatory neurotransmitter that can stimulate and produce a long-lasting increase in the activity of pain sensing and transmitting neurons in the central nervous system.

Research on prevention also moves ahead. Ways to inhibit the spread of abnormal electrical activity across the cortex have been developed in animal models and may be a future strategy for humans. In addition, the new acute treatment strategies inhibiting trigeminal nerve activation may play a role in preventing migraine, as well.

A CALL TO ACTION

Contrary to popular belief, migraine and other primary headache disorders are neither the “common cold” of neurological disorders, nor an indication of a neurotic individual unable to handle the stresses of daily life. We now realize migraine is an inherited, highly disabling, and unpredictable neurological disorder that exacts a heavy toll from millions of sufferers, their families, and society. Fortunately, tremendous advances in molecular biology and our ability to image the living brain have uncovered the mechanisms and speciﬁc brain regions involved in initiating and maintaining the migraine attack, and enabled the development of highly speciﬁc and effective treatments.

Our knowledge continues to move at a rapid pace. New targets for treatment are being identiﬁed, drug discovery programs are ﬂourishing, and preliminary results look promising indeed. As our ability to probe with scientiﬁc precision into the molecular mechanisms that initiate each attack improves, the development of therapies that target these mechanisms and prevent attacks from ever occurring will follow in short order. Along with this must come a paradigm shift in the way headache patients are viewed by treating physicians, the general public, and employers. A medical condition that afﬂicts so many and yet is eminently treatable, provides a tremendous opportunity for physicians to practice our art, reduce suffering, and improve the quality of life for our patients—this was and is our calling. Our patients will be forever grateful if we respond.

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About Cerebrum

Bill Glovin, editor Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board Joseph T. Coyle, M.D., Harvard Medical School Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital Robert Malenka, M.D., Ph.D., Stanford University School of Medicine Bruce S. McEwen, Ph.D., The Rockefeller University Donald Price, M.D., The Johns Hopkins University School of Medicine